Since the discovery of the opiate receptor and endogenous opioid ligands (endorphins), there has been considerable speculation regarding the role of this endogenous opioid system in behavior and mental illness. The major goal of this project is to use available clinical research strategies to study endorphins in human behavior and psychiatric illness. The Unit has tested the behavioral effects of intravenously administered naloxone, a pure narcotic antagonist, and of beta-endorphin, an endogenous opioid peptide, in both affectively ill and schizophrenic patients. A sensitive radioreceptor assay used to determine opioid activity in human CSF and plasma has been developed and used in conjunction with radioimmunoassay for beta-endorphin to study endogenous opioid function in medication-free and drug treated psychiatric patients. We have now completed a high dose-response naloxone study in normal volunteers. Results indicate that considerably higher naloxone doses than previously thought are needed to block the endogenous opioid system. High dose naloxone effects support hypothesized roles for the endogenous opioid system in mood and physiologic regulation.